A wide range of xenobiotic substances, including many useful drugs, are metabolized by hepatic cytochrome P-450 enzymes to toxic electrophilic species, which can cause liver necrosis and lead to death. Such drugs include many antibiotics, antiinflammatory drugs, analgesics, halogenated hydrocarbons and antitumor drugs. The protective mechanisms of mammalian cells employ the co-enzyme, glutathione (GSH), which is important in maintaining the structural integrity of cell and organelle membranes and in the synthesis of microtubules and macromolecules. See C. D. Klassen et al., Fundamental and Applied Toxicology, 5, 806 (1985). Stimulation of GSH synthesis in rat renal epithelial cells and stomach cells has been found to protect the cells from the toxic effects of cyclophosphamide and serotonin, respectively. Conversely, inhibition of glutathione synthesis has been found to have the following effects: (a) decreased cell viability, (b) increased sensitivity of cells to the effects of irradiation, (c) increased sensitivity of tumor cells to peroxide cytolysis, (d) decreased synthesis of prostaglandin E and leukotriene C and (e) selective destruction of trypanosomes in mice.
It has been hypothesized that delivery of L-cysteine to mammalian cells would elevate GSH levels by supplying this biochemical GSH precursor to the cell. However, cysteine itself is toxic when administered to mammals, and is rapidly degraded.
In previous studies, it was shown that N-acetyl-L-cysteine, L-2-oxothiazolidine-4-carboxylate, as well as 2(R,S)-n-propyl-, 2(R,S)-n-pentyl and 2(R,S)-methylthiazolidine-4R-carboxylate can protect mice from heptatotoxic dosages of acetaminophen. See H. T. Nagasawa et al., J. Med. Chem., 27, 591 (1984) and A. Meister et al., U.S. Pat. No. 4,335,210. L-2-Oxothiazolidine-4-carboxylate is converted to L-cysteine via the enzyme 5-oxo-L-prolinase. As depicted in FIG. 1, compounds of formula 1, e.g., wherein R=CH.sub.3, function as prodrug forms of L-cysteine (2), liberating this sulfhydryl amino acid by nonenzymatic ring opening and hydrolysis. However, the dissociation to yield L-cysteine necessarily releases an equimolar amount of the aldehyde (3), RCHO. In prodrugs in which R is an aromatic or an alkyl residue, the potential for toxic effects is present.
Therefore, a need exists for cysteine prodrugs which are effective to raise cellular glutathione levels, e.g., which can act as hepatoprotective agents, while not releasing toxic aldehydes during intracellular degradation.